Investigation of the sympathetic nervous system and catecholamine kinetics may provide insight into coronary and systemic blood flow regulation. Although alpha-adrenoceptor blockade produces vasodilatation, blockade of presynaptic alpha-2 receptors stimulates release of norepinephrine. To assess the impact of systemic alpha-2 receptor blockade on the heart, yohimbine was infused intravenously in 12 patients with normal coronary arteries. We measured systemic and coronary hemodynamics and systemic and coronary flow and resistance, as well as norepinephrine spillover into the systemic artery and coronary and femoral veins. Yohimbine increased the spillover of norepinephrine into the great cardiac vein, artery and femoral vein by 117, 157, and 852% respectively. Systemic alpha-2 blockade increased cardiac norepinephrine spillover with no change in coronary vascular resistance, contrasting with increased resistance and much larger increases in norepinephrine spillover in the forearm. Thus, direct vasodilator effects of alpha-2 blockade by yohimbine are overwhelmed by vasoconstrictor effects due to a release of norepinephrine, especially in the systemic circulation.